Trypanosoma cruzi is a protozoan parasite which causes human Chagas' disease, a major health problem in Latin America. Infection with T. cruzi causes non-specific immune suppression which may provoke related pathologies associated with Chagas' disease. We are studying T. cruzi infections in mice as a model for infection-induced suppression of immune responsiveness. Mice with chronic infections, the form most commonly seen in humans, have suppressed T cell dependent immune responses, including antibody production and the generation of cytotoxic T lymphocytes (CTL). We and others have demonstrated that immune responsiveness can be restored with interleukin-2 (IL-2), both in vitro and in vivo. The aims of this proposal are to define immune suppression in mice with T. cruzi infection at the molecular level. A primary emphasis will be on the involvement of cytokines in the immune response, both antibody and CTL production, with particular importance placed on therapeutic restoration of immune responsiveness in vitro and in vivo. Mechanisms by which cytokines function to restore immune responsiveness will be determined. For example, we have found that IL-1 is able to completely restore suppressed antibody production in infected mice. Using molecular probes, we will determine whether IL-2 is increased in these spleen cells following IL-1 treatment. We will examine spleen cells from infected mice for their ability to respond to antigenic and mitogenic stimuli with the production of cytokine and/or cytokine mRNA. We will determine whether suppressed IL-2 production is pre- or post-transcriptional or via post-translational regulation. A similar approach will be used to analyze production f other cytokines. The regulation of cytokine production by cells from infected mice will be analyzed. Immortalized macrophage hybridomas and T cell clones from infected mice will be generated to further these studies.